Immunosenescence is the age-dependent deterioration of immune function that contributes to increased susceptibility of the elderly to infection. It is a hallmark of aging and is known to contribute to age-dependent increases in mortality, morbidity, and potentially cancer. The mammalian immune response consists of two components: an adaptive (also called acquired) response and an innate response. Innate immunity involves such things as recognition of microorganisms, secretion of anti-microbial peptides, and recruitment of the adaptive response. Aspects of both the adaptive and innate response are subject to deterioration with advancing age. Mechanisms of innate immunity are highly conserved across species, and the success of Drosophila as a model system in both the genetics of innate immunity and the genetics of aging make it an ideal candidate for investigating the interaction between these two processes. There are indications that innate immunity and aging are closely linked in this species. Dramatic increases in transcript representation with age have been observed for several key immune-regulated genes, and some, but not all, of these increases were linked to the rate of aging because they were ameliorated in long-lived flies. The primary goals of this application are to extend the intriguing observations described above and to systematically investigate immune function in the context of physiological changes that accompany normal aging in Drosophila. This work will provide the first description of the impact of aging on fly immunity, will establish preliminary data for future funding applications concerning the genetics of immunosenescence, and will test the viability of Drosophila as a model system for this type of research. We will test the hypothesis that the innate immune response is a causative factor in determining aging-related mortality. We will also measure the physiological and transcriptional response to controlled exposure to infectious agents and determine whether lifespan in Drosophila is limited by natural exposure to pathogens.